meeting, 2007) as well as to assess the long-term outcome in comparison to naturalhistory (i.e., longitudinal study of Project 9, Bjoraker).

Conclusion and significance: This two-year pilot study will provide an initialassessment of the potential outcome measures that are sensitive for infantile TSD,and provide and initial Phase I/II assessment of hexavec AAV gene therapy for this dis-order providing the basis for an ongoing and expanded clinical trial.

doi:10.1016/j.ymgme.2008.11.152

152. Pulmonary disease and exercise tolerance in boys with fabry disease

William Wilcox, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Fabry disease (FD) is an X-linked inborn error of metabolism characterized bydecreased or absent activity of alpha-galactosidase A. Subsequent deposition of GL-3 causes acroparesthesias, angiokeratoma, strokes, arrhythmias, hypertrophic cardio-myopathy, gastrointestinal symptoms, hypohidrosis, temperature and exercise intol-erance, and kidney failure. Enzyme replacement therapy (ERT) effectively reduces GL-3 accumulation, improving many clinical symptoms and stabilizing kidney function.

Pulmonary involvement is an under-recognized component of FD. In our center,the majority of FD patients had abnormal pulmonary function tests (PFTs) withreduced FEF25-75 and decreased V02max on treadmill testing. Furthermore, the dia-stolic blood pressure declined with increasing exercise, an abnormality that corre-lated with fatigue in females. In the few patients we followed as part of a clinicaltrial of ERT, exercise testing improved with ERT.

The symptoms of Fabry disease most often experienced by children include pain,gastrointestinal dysfunction, hypohidrosis, and abnormal heat and cold tolerance. Inaddition to these symptoms, children often complain of exercise intolerance.

Hypothesis: Exercise intolerance is common in boys with FD and correlates withabnormal treadmill testing and PFTs.

Specific aim: Determine the frequency and severity of pulmonary disease andexercise intolerance in boys with FD. In this pilot study, 20 FD boys between age 8and 18 who have not been treated with ERT will be evaluated with standard FabryRegistry assessments as well as urine GL-3, PFTs and treadmill testing.

Significance: Although GL-3 accumulation is present at birth and is progressive,ERT is generally withheld until there is significant pain or GI symptoms. With somecases of significant early major organ involvement, rational guidelines for monitoringand treatment of children are desperately needed. We expect PFTs and exercise test-ing will be important clinical parameters for assessing FD children.

doi:10.1016/j.ymgme.2008.11.153

153. Syngeneic Bone marrow transplantation in a murine model of mucopoly-saccharidosis type I

Daniel Wolf, Zhenhong Nan, Kelly Podetz-Pedersen, Jennifer Gori, Brenda Koniar,Chester Whitley, Walter Low, R. Scott McIvor, University of Minnesota-Twin Cities,Minneapolis, MN, USA

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive inherited diseasecaused by deficiency of the glycosidase alpha-L-iduronidase (IDUA). IDUA is requiredfor the degradation of the glycosaminoglycans (GAG) heparan sulfate and dermatansulfate, and deficiency of the enzyme leads to lysosomal storage of these substrates.Specific mutations in the IDUA gene lead to the most severe phenotype, Hurler syn-drome. Recently, IDUA-deficient mouse models of MPS I have become available, pro-viding a setting for evaluation of therapeutic approaches for this disease. Currently,the standard of care for severe MPS I patients is allogeneic bone marrow transplanta-tion (BMT). However, the effectiveness of BMT has not yet been characterized in theMPS I mouse model. We have engrafted a cohort (n = 33) of 4–9 week-old IDUA/ ani-mals with wild-type donor marrow at high levels (50–90%). These animals displayedan increased lifespan compared to untreated control animals. Brain, heart, liver,spleen, kidney, and lung tissues were harvested from 9 engrafted animals that sur-vived to 80 weeks of age. To assess the levels of metabolic correction achieved, assayswill be conducted to determine levels of IDUA enzyme activity and GAG accumulationin these tissues. Additionally, brain sections will be evaluated histologically to deter-mine the extent and character of cell types engrafting in the CNS. We intend to char-acterize the quantitative relationship between level of donor cell engraftment and thecorrelated extent of metabolic correction achieved in individual animals. Our goal isto determine the extent to which donor-derived cells penetrate the CNS and the celltypes that arise from donor-derived material. Results from this animal study may pro-vide useful information in determining the level of engraftment needed to achievemetabolic correction and the potential benefit in preventing CNS manifestations inhumans.

doi:10.1016/j.ymgme.2008.11.154

154. Disease stability in patients with Niemann–Pick disease type C treated withmiglustat

Ed Wraitha, Darlenn Vecchiob, Elizabeth Jacklina, Cicile Luzyc, Ruben Giorginoc, MarcPattersond, aRoyal Manchester Children s Hospital, Manchester, Greater Manchester, UK,bColumbia University, New York, NY, USA, cActelion Pharmaceuticals Ltd., Allschwil,Switzerland, dMayo Clinic, Rochester, MN, USA

Introduction: Niemann–Pick disease type C (NP-C) is an invariably progressiveneurological disorder. The clinical trial, OGT 918-007, in juveniles/adults (e12 years)and in children (4–11 years) with NP-C showed improvement or stabilisation of dis-ease progression in patients receiving up to 66 months of miglustat. We present apost-hoc analysis of major parameters of neurological disease progression from thistrial.

Methods: Patients who received at least 12 months’ miglustat (200 mg t.i.d. ordoses adjusted by BSA in children) and had baseline and last-visit data were evalu-ated. Assessments included: (1) horizontal saccadic eye movement-alpha (HSEM-al-pha), (2) swallowing, (3) Standard Ambulation Index (SAI) and (4) Mini-MentalState Evaluation (MMSE) (performed in adults/juveniles only). Patients were classi-fied as having stable disease if there was no deterioration in swallowing, SAI andMMSE, or if only HSEM-alpha deteriorated.

Results: 19 adults/juveniles and 10 children (mean SD age: 22.6 9.4 and 7.2 2.4years, respectively) were included. Among patients with evaluable data, HSEM-alpha-was improved or stable in 11/18 (61.1%) adults/juveniles and 6/9 (66.7%) children.Swallowing was improved or stable in 15/19 (78.9%) adults/juveniles and remainedstable in 9/9 (100%) children. Ambulation was improved or stable in 17/19 (89.5%)adults/juveniles and remained stable in 8/10 (80.0%) children. MMSE scores were im-proved or stable in 14/18 (77.7%) adults/juveniles. In total, 21/29 (72.4%) patients(including 8 children) showed stable disease.

Conclusions: These results indicate stabilisation of key parameters of neurologicaldisease progression in most NP-C patients treated with miglustat.

doi:10.1016/j.ymgme.2008.11.155

155. High Throughput screen for identifying small molecule modulators of alpha-glucosidase for the potential treatment of Pompe disease

Wei Zhenga, Omid Motabarb, Ke Liua, Ehud Goldinb, Noel Southalla, Juan Marugana,Christopher Austina, Ellen Sidranskyb, aNIH Chemical Genomics Center, National HumanGenome Research Institute, NIH, Bethessda, MD, USA, bMedical Genetics Branch, NationalHuman Genome Research Institute, NIH, USA

Small molecule chaperones have recently emerged as an alternative therapy forlysosomal storage disorders caused by protein misfolding and mistrafficking. Deoxy-nojirimycin, an iminosugar based alpha-glucosidase inhibitor has been reported tohave a chaperone effect, correcting the misfolding and mistrafficking of mutantalpha-glucosidase. However, the enhancement of enzyme activity by the chaperoneaction of an inhibitor must be balanced against the direct inhibition of the enzyme.Thus, an enzyme activator with chemical chaperone activity should have better ther-apeutic potential than an inhibitor. Currently, no small molecule alpha-glucosidaseactivators are known. We performed high throughput screening of a 240,000 com-pound library using an enzyme assay to identify small molecule modulators ofalpha-glucosidase. Several structural classes of activators and inhibitors were identi-fied from the screening. The activities of these compounds were confirmed in enzymeassay using both the recombinant enzyme and an enzyme preparation isolated fromhuman spleen tissue. The pharmacological properties and activities of these com-pounds in a cell-based assay will be presented.

doi:10.1016/j.ymgme.2008.11.156

156. The role of neuropsychological testing in clinical research on lysosomaldiseases

Richard Ziegler, Kendra Bjoraker, Elsa Shapiro, University of Minnsota, Minneapolis, MN,USA

Most lysosomal diseases have some degree of central nervous system (CNS)involvement. The FDA and the NIH now recognize the neurodevelopmental effectsof disease and treatment, and require monitoring of such effects. Neuropsycholog-ical monitoring systems require acquisition of natural history data through longi-tudinal assessment, as well as sensitivity to treatment effects, underlying braincircuitry, and course and prognosis for clinical and research utility. Neuropsycho-logical markers must be developed that assess treatment efficacy for clinical tri-als. Also, they must have clinical relevance to make appropriate recommendationsfor educational, behavioral and rehabilitative therapies as well as assess quality-of-life.

S46 Abstracts / Molecular Genetics and Metabolism 96 (2009) S12–S47